Bacteriuria and pyuria are uniformly present in patients who have indwelling urinary catheters. Antimicrobial therapy may transiently eradicate the bacteria, but bacteriuria promptly recurs, and the infecting bacteria become progressively resistant to antibiotics. No mode of treatment is known to eliminate chronic, subclinical infections or to prevent intercurrent, clinically important infections.
Universal guidelines intended to prevent or delay catheter-associated urinary tract infections (CAUTI) include the following: avoidance of unnecessary catheterization; use of a trained professional to insert and care for the catheter; prompt removal of the catheter when no longer needed; maintenance of sterile closed drainage; maintenance of good drainage; minimal manipulation of the system; use of a condom or suprapubic catheter instead of a urethral catheter; and separation of catheterized patients (NIDRR, “SCI Nurs 10(2): 49-61 Jan. 27-29, 1992; Maki, D. G. and P. A. Tambyah, Emerg Infect Dis 7(2): 342-7(2001)) from both each other and other patients in the hospital. Most measures that have been tested have not shown effectiveness in randomized clinical trials, however, and some are not applicable to patients with a neurogenic bladder.
Technologies have been tested for prevention of CAUTI, including use of anti-infective lubricants when inserting the catheter, use of sealed catheter-collection tubing junctions or anti-reflux valves, continuous irrigation of the catheterized bladder with an anti-infective solution through a triple lumen catheter, and periodic instillation of an anti-infective solution into the collection bag. However, these technologies have not been confirmed to be effective in randomized clinical trials (Maki and Tambyah, supra).
The use of anti-infective catheter material to reduce the incidence of CAUTI is under investigation. Catheters impregnated with antimicrobial agents may have some benefit, although studies have been small (Maki and Tambyah, supra). Silver-oxide coated catheters did not show efficacy in large randomized trials, and tests of the ability of a silver alloy hydrogel catheter to decrease infection produced conflicting trial results (Wong, E. and T. Hooton, “Guideline for prevention of catheter-associated urinary tract infections.” Center for Disease Control and Prevention (1981); Rupp, M. E., T. Fitzgerald, et al., Am J Infect Control 32(8): 445-50 (2004).
Antimicrobial (e.g., antibiotic and/or antiseptic) treatment of asymptomatic urinary tract infections (UTI) in catheterized patients has not been shown to be of benefit, as treated and untreated catheterized patients have a similar prevalence of infection a few weeks after the end of treatment, and an equal likelihood of developing symptomatic episodes of UTI (Nicolle, L. E., Drugs Aging 22(8): 627-39 (2005). Additionally, antimicrobial treatment of asymptomatic CAUTI has been associated with the emergence of drug-resistant organisms, complicating management when a symptomatic infection does occur.
Given the difficulty of eradicating bacteriuria in a patient with long-term bladder catheterization, the problem of chronic bacteriuria and recurrent UTI in catheter-dependent persons is not likely to be resolved by the use of antimicrobial agents. Studies have indicated that pre-colonization of the bladder with certain non-pathogenic strains of E. coli is a safe and effective way of preventing or reducing the in vitro incidence of urinary catheter colonization by a wide variety of uropathogens.
Escherichia coli 83972 is a clinical isolate associated with asymptomatic bacteriuria (Andersson et al., 1991, Infect. Immun. 59:2915-2921) and the strain has been used to successfully colonize bladders of human volunteers. E. coli HU2117, a variant of 83972 having a deleted papG83972 gene, has also been shown to successfully colonize the bladders of human subjects (Hull, et al., 2002, Infection and Immunity, 70(11):6481-6481).
However, existing methods of pre-inoculation of the urinary tract are cumbersome. In some instances, pre-colonization is accomplished by introducing a liquid preparation of bacteria directly into the bladder. Using this approach, the patient is first treated with appropriate antibiotics to sterilize the urine. After an antibiotic-free interval, the patient is catheterized and the bladder is emptied. Thirty milliliters of E. coli 83972 (105 colony-forming units (CFU)/mL) is instilled in the bladder and the catheter is removed. The procedure is repeated once daily for 3 days. According to individual study protocols, subsequent urine samples are taken to assess host response parameters, and to prove the success or failure of the colonization procedure.
Other groups have investigated pre-colonization by incubating the catheter itself in a broth containing the non-pathogenic microbe. For example, in published protocols, a catheter is immersed in a bacterial suspension for 48 hours to form a biofilm on the catheter. The resulting biofilms generally contain 5×104 to 1×105 colony forming units (cfu) of E. coli 83972 per centimeter of catheter tubing. The catheter is then inserted using conventional catheter lubrication (such as SteriLub lubricant, SurgiLube lubricant, KY Jelly) prior to insertion. It is believed that the biofilm on the catheter acts as a reservoir that can help keep the bladder colonized.
Such methods of delivering a probiotic to the bladder require physicians and hospitals to develop new procedures for the growth and administration of the microbes, and for the handling and use of catheters. There remains a need for improved methods and formulations for delivery of probiotic microbes to a subject. There also remains a need for improved methods of producing and using such formulations.